The Role of Spreading Depolarizations in Concussion-like Injuries

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Approximately 3.8 million sports-related concussions occur each year. Diagnosis and treatment of these injuries is usually based on behavioral and cognitive deficits that are not always affected immediately following an injury. The pathophysiology underlying acute phases of concussion deficits are poorly understood but may involve a phenomenon termed spreading depolarization (SD). SDs are large propagating waves of complete depolarization that result in a profound but transient depression of brain activity. Although SDs events have been studied for decades in the context of moderate and severe traumatic brain injuries, only recently have these events been suggested to occur in concussion. These observations and our preliminary data raise the intriguing possibility that SDs underlie some of the short and long-term consequences of concussions. The presence of SDs during a concussion needs to be validated, and it is not yet known whether recurring SDs in the following hours to days following a concussion contributes to persistent cognitive deficits. Our long-term goal is to improve diagnosis and treatments for concussions and to identify strategies to enhance brain recovery and repair following a concussion. The objectives of this proposal are to determine whether SDs contribute to the symptoms of a concussion and identify the deleterious effects of a second concussion prior to brain recovery. My central hypothesis is that SDs are an important underlying mechanism of a concussion that can leave the brain susceptible to subsequent damage from a second impact and/or recurrent SDs resulting in short-term cognitive deficits. The rationale for these studies is that they will directly test the role of SDs as an underlying and targetable mechanism of concussions and the prolonged deficits associated with concussions. SA1: will test the hypothesis that concussion-like impacts initiate SDs. SA2: test the hypothesis that an impact-induced SDs will result in short and long-term deficits in CBF that renders the brain vulnerable to subsequent impacts and damage. SA3: will test the hypothesis that concussion-like impacts produce recurrent SDs in conscious and moving animals and short-term cognitive deficits.